Animal models of virus-induced demyelination have relevance to the human disease multiple sclerosis (MS). We are particularly interested in viral infections in which myelin degeneration may be immune-mediated. The most important model of this type is the murine infection with Theiler's virus (TV). Mice infected intracerebrally with the DA strain of TV develop a bi-phasic illness characterized by a first transient phase of grey matter inflammation and a second chronic phase of white matter inflammatory demyelination. Immunosuppression of infected animals results in the prevention of both inflammatory response and demyelination suggesting that myelin injury is mediated through the host-immune response rather than being produced by primary cytocidal viral activity. We recently demonstrated that animals infected with attenuated cell-adapted virus develop a slower disease with longer incubation period and that myelin degeneration occurs in a recurrent fashion. In addition we showed that demyelinated spinal cords may be extensively remyelinated by Schwann cells in the infection by attenuated virus. By ultrastructural immunoperoxidase techniques we have also demonstrated that virus persists for several months in neuronal processes, astrocytes, mononuclear cells and macrophages. Macrophages are particularly rich in viral inclusions and there is evidence that these cells may be important in the establishment of viral persistance. Research goals for the coming year are 1) to further investigate the role of macrophages as effector cells in the production of demyelination by using inhibitors of neutral proteases which are secreted by macrophages during the inflammatory response; 2) to investigate the source of Schwann cells which invade and remyelinate affected spinal cords. These studies will be conducted using 3H-thymidine as a marker for proliferating Schwann cells for light and ultrastructural autoradiography; 3) to extend these studies to other viral models like Venezuelan Equine Encephalomyelitis virus (VEEV) infection in which preliminary studies suggested that demyelination may be produced through the host-immune response. By studying different models produced by unrelated viruses, it is hoped that a common pathogenetic mechanism of myelin injury will be identified.